Project Summary Apical periodontitis (AP) is a highly prevalent and debilitating pathological condition marked by bone resorption and pain as result of dental infections. Many elegant studies have revealed the functions of immune cells and inflammatory mediators in AP. Despite AP being densely innervated by trigeminal ganglia (TG) fibers, the participation of these afferents in this disease process is largely unknown. Our preliminary data demonstrate that TG neurons regulate AP lesion development. The objective of this proposal is to understand how TG fibers control AP development, which remains a large gap in knowledge. We, for the first time, propose to investigate neurons/non-neuronal cell interaction in control of AP development for each of four major subclasses of TG neurons. This is novel and critically important strategy in approaching research on regulation of AP development by sensory neurons, since each neuronal sub-class has distinct function and biochemical make up, including unique sets of receptors, ion channels and neuropeptides. Hence, it is possible that regulatory potential of TG neuronal subsets could dramatically vary; and even produce opposite effects on osteoclasts and osteoblasts. So according to literature and preliminary experiments, we designed a novel strategy on study AP development by TG neurons. Our central hypothesis is that in response to infection certain subclasses of TG afferents inhibit bone resorption in apical periodontitis via the regulation of osteoclastic and osteoblastic activities. This hypothesis will be tested in: Aim 1 examining role of different subclasses of TG afferents in inhibiting bone resorption and immunological responses in a murine model of infection-induced AP; Aim 2 defining involvement of different subclasses of TG neurons on regulation of osteoclastic and osteoblastic functions; and Aim 3 defining and identifying the released soluble factor(s) from different subclasses of TG neurons and their contribution to modulation of osteoclast and osteoblast functions. We believe that knowledge generated by this application will have a substantial positive impact from both scientific and clinical perspectives. Scientifically, this is the principally novel approach in investigation of AP using subclass-specific TG mouse lines. Moreover, the generated new insight into interactions between neurons and DCS remodeling will open pathways for further scientific advancement. Clinically, identification of neuronal regulatory mechanisms could offer novel strategies and, importantly, targets for developing anti-AP therapeutics.